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Background & Aims: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with advanced fibrosis., Methods: This prospective, cross-sectional, familial study consisted of a derivation cohort from San Diego, California, and a validation cohort from Helsinki, Finland. This study included consecutive adult probands (n = 242) with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 of their first-degree relatives. All included probands and first-degree relatives underwent evaluation of liver fibrosis, the majority by magnetic resonance elastography., Results: A total of 396 first-degree relatives (64% male) were included. The median age and body mass index were 47 years (interquartile range, 32-62 y) and 27.6 kg/m 2 (interquartile range, 24.1-32.5 kg/m 2 ), respectively. Age (1 point), type 2 diabetes (1 point), obesity (2 points), and proband with NAFLD and advanced fibrosis (2 points) were predictors of advanced fibrosis among first-degree relatives in the derivation cohort (n = 220) and formed the NAFLD Familial Risk Score. The area under the receiver operator characteristic curve of the NAFLD Familial Risk Score for detecting advanced fibrosis was 0.94 in the validation cohort (n = 176). The NAFLD Familial Risk Score outperformed the Fibrosis-4 index in the validation cohort (area under the receiver operator characteristic curve, 0.94 vs 0.70; P = .02)., Conclusions: The NAFLD Familial Risk Score is a simple and accurate clinical tool to identify advanced fibrosis in first-degree relatives. These data may have implications for surveillance in NAFLD., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721., Competing Interests: Declaration of Competing Interest FEM, SA, KW, JC, MA, EMG, SF, MRG, JC, IFL, RA, RSG, JMP, JB, VR, MW, SP, MA, RF, LM, ET, ME, PL, ATH, GP, HYJ, KP and PMB declare no conflicts of interest. MP is a shareholder in Perspectum Ltd. EMT is a shareholder in Perspectum Ltd. SA is currently employed by Boehringer Ingelheim (but was not during his participation in the project). GPA has served as a consultant and an advisory board member for Pfizer Inc., Inventiva Pharma, GlaxoSmithKline and KaNDy Therapeutics; he has been a consultant to BerGenBio ASA, Median Technologies, FRACTYL, Amryt Pharmaceuticals and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. CA declares the following potential conflicts of interest: Hologic: Support of study and expert; Guerbet: Member of board, PI of study; Siemens: Expert. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento; and a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer. She has also received a research grant from Gilead Sciences for fatty liver research. AG served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; received research funding from Intercept, Falk, Novartis. JMS reports consultancy for BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Pfizer, Roche, Sanofi; received research funding from Gilead Sciences and was on the speaker's bureau for Falk Foundation MSD Sharp & Dohme GmbH. MJS and PH are employed by Antaros Medical AB, Mölndal, Sweden. ES is employed by Perspectum Ltd., Oxford, UK. RB is a shareholder and employed (CEO) by Perspectum Ltd., Oxford, UK. KP and MK are employed by Resoundant Inc., Rochester, MN, USA. RLE and the Mayo Clinic have intellectual property rights and a financial interest in magnetic resonance elastography technology. AT is employed by ADVANZPHARMA, Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, United Kingdom. HC is employed by Boehringer Ingelheim Pharma GmbH & Co. MM is employed by Novartis AG, Basel, Switzerland. CY is employed by Pfizer Inc., Lake Mary, FL, USA. TT was employed by Pfizer at the time of her involvement with the project. QMA is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. QMA has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. SN is a shareholder in Perspectum Ltd. SAH has research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, Viking. He has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, HIghtide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Pathologists quantify liver steatosis as the fraction of lipid droplet-containing hepatocytes out of all hepatocytes, whereas the magnetic resonance-determined proton density fat fraction (PDFF) reflects the tissue triacylglycerol concentration. We investigated the linearity, agreement, and correspondence thresholds between histological steatosis and PDFF across the full clinical spectrum of liver fat content associated with non-alcoholic fatty liver disease., Methods: Using individual patient-level measurements, we conducted a systematic review and meta-analysis of studies comparing histological steatosis with PDFF determined by magnetic resonance spectroscopy or imaging in adults with suspected non-alcoholic fatty liver disease. Linearity was assessed by meta-analysis of correlation coefficients and by linear mixed modelling of pooled data, agreement by Bland-Altman analysis, and thresholds by receiver operating characteristic analysis. To explain observed differences between the methods, we used RNA-seq to determine the fraction of hepatocytes in human liver biopsies., Results: Eligible studies numbered 9 (N = 597). The relationship between PDFF and histology was predominantly linear (r = 0.85 [95% CI, 0.80-0.89]), and their values approximately coincided at 5% steatosis. Above 5% and towards higher levels of steatosis, absolute values of the methods diverged markedly, with histology exceeding PDFF by up to 3.4-fold. On average, 100% histological steatosis corresponded to a PDFF of 33.0% (29.5-36.7%). Targeting at a specificity of 90%, optimal PDFF thresholds to predict histological steatosis grades were ≥5.75% for ≥S1, ≥15.50% for ≥S2, and ≥21.35% for S3. Hepatocytes comprised 58 ± 5% of liver cells, which may partly explain the lower values of PDFF vs. histology., Conclusions: Histological steatosis and PDFF have non-perfect linearity and fundamentally different scales of measurement. Liver fat values obtained using these methods may be rendered comparable by conversion equations or threshold values., Impact and Implications: Magnetic resonance-proton density fat fraction (PDFF) is increasingly being used to measure liver fat in place of the invasive liver biopsy. Understanding the relationship between PDFF and histological steatosis fraction is important for preventing misjudgement of clinical status or treatment effects in patient care. Our analysis revealed that histological steatosis fraction is often significantly higher than PDFF, and their association varies across the spectrum of fatty liver severity. These findings are particularly important for physicians and clinical researchers, who may use these data to interpret PDFF measurements in the context of histologically evaluated liver fat content., Competing Interests: RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharm, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics. In addition, RL’s institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. RL is a co-founder of LipoNexus Inc. CBS reports research grants from ACR, Bayer, GE, Gilead, Pfizer, Philips, Siemens; equipment loans from GE; lab service agreements with Enanta, Gilead, ICON, Intercept, Nusirt, Shire, Synageva, Takeda; institutional consulting for BMS, Exact Sciences, IBM-Watson, Pfizer; Personal consulting for Blade, Boehringer, Epigenomics, and Guerbet; receipt of royalties and/or honoraria from Medscape and Wolters Kluwer; ownership of stock options in Livivos; unpaid advisory board position in Quantix Bio. CBS serves as Chief Medical Officer for Livivos (unsalaried position). Unrelated to this paper, MP declares stock ownership in Perspectum Ltd. All other authors state that no conflicts of interest regarding this manuscript exist. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background and Aims: The susceptibility of low-density lipoprotein (LDL) to aggregation predicts atherosclerotic cardiovascular disease. However, causes of interindividual variation in LDL lipid composition and aggregation susceptibility remain unclear. We examined whether the lipid composition and aggregation susceptibility of LDL reflect the lipid composition of the human liver., Methods: Liver biopsies and blood samples for isolation of LDL particles were obtained from 40 obese subjects (BMI 45.9 ± 6.1 kg/m 2 , age 43 ± 8 years). LDL was isolated using sequential ultracentrifugation and lipidomic analyses of liver and LDL samples were determined using ultra-high performance liquid chromatography-mass spectrometry. LDL aggregation susceptibility ex vivo was analyzed by inducing aggregation by human recombinant secretory sphingomyelinase and following aggregate formation., Results: The composition (acyl carbon number and double bond count) of hepatic triglycerides, phosphatidylcholines, and sphingomyelins (SMs) was closely associated with that of LDL particles. Hepatic dihydroceramides and ceramides were positively correlated with concentrations of the corresponding SM species in LDL as well with LDL aggregation. These relationships remained statistically significant after adjustment for age, sex, and body mass index., Conclusions: Lipid composition of LDL reflects that of the human liver in obese patients. Changes in hepatic sphingolipid metabolism may contribute to interindividual variation of LDL lipid composition and susceptibility to aggregation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.Ö. and M.R. have a patent pending on the LDL aggregation method., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Background: QRS duration and corrected QT (QTc) interval have been associated with sudden cardiac death (SCD), but no data are available on the significance of repolarization component (JTc interval) of the QTc interval as an independent risk marker in the general population., Objective: In this study, we sought to quantify the risk of SCD associated with QRS, QTc, and JTc intervals., Methods: This study was conducted using data from 3 population cohorts from different eras, comprising a total of 20,058 individuals. The follow-up period was limited to 10 years and age at baseline to 30-61 years. QRS duration and QT interval (Bazett's) were measured from standard 12-lead electrocardiograms at baseline. JTc interval was defined as QTc interval - QRS duration. Cox proportional hazards models that controlled for confounding clinical factors identified at baseline were used to estimate the relative risk of SCD., Results: During a mean period of 9.7 years, 207 SCDs occurred (1.1 per 1000 person-years). QRS duration was associated with a significantly increased risk of SCD in each cohort (pooled hazard ratio [HR] 1.030 per 1-ms increase; 95% confidence interval [CI] 1.017-1.043). The QTc interval had borderline to significant associations with SCD and varied among cohorts (pooled HR 1.007; 95% CI 1.001-1.012). JTc interval as a continuous variable was not associated with SCD (pooled HR 1.001; 95% CI 0.996-1.007)., Conclusion: Prolonged QRS durations and QTc intervals are associated with an increased risk of SCD. However, when the QTc interval is deconstructed into QRS and JTc intervals, the repolarization component (JTc) appears to have no independent prognostic value., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Ambulance patients are usually transported to the hospital in the emergency medical service (EMS) system. The aim of this study was to describe the non-conveyance practice in the Helsinki EMS system and to report mortality following non-conveyance decisions., Methods: All prehospital patients ≥16 years attended by the EMS but not transported to a hospital during 2013-2017 were included in the study. EMS mission- and patient-related factors were collected and examined in relation to patient death within 30 days of the EMS non-conveyance decision., Results: The EMS performed 324,207 missions with a patient during the study period. The patient was not transported in 95,909 (29.6%) missions; 72,233 missions met the study criteria. The patient mean age (standard deviation) was 59.5 (22.5) years; 55.5% of patients were female. The most common dispatch codes were malaise (15.0%), suspected decline in vital signs (14.0%), and falling over (12.9%). A total of 960 (1.3%) patients died within 30 days after the non-conveyance decision. Multivariate logistic regression analysis revealed that mortality was associated with the patient's inability to walk (odds ratio 3.19, 95% confidence interval 2.67-3.80), ambulance dispatch due to shortness of breath (2.73, 2.27-3.27), decreased level of consciousness (2.72, 1.75-4.10), decreased blood oxygen saturation (2.64, 2.27-3.06), and abnormal systolic blood pressure (2.48, 1.79-3.37)., Conclusion: One-third of EMS missions did not result in patient transport to the hospital. Thirty-day mortality was 1.3%. Abnormalities in multiple respiratory-related vital signs were associated with an increased likelihood of death within 30 days., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity., Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD., Design: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3)., Setting: Tertiary referral center., Patients: We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m2]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS., Main Outcome Measures: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage ≥F3 fibrosis or nonalcoholic steatohepatitis with ≥F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]., Results: The scores with an AUROC ≥0.85 to identify ≥F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out ≥F3 fibrosis in groups with BMIs <30.0, 30.0 to 39.9, and ≥40.0 kg/m2. This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose ≥F3 fibrosis., Conclusions: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD., Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D 5 -glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D 2 O (n = 61)., Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD., Conclusions: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD., Lay Summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL 1 (very low-density lipoprotein) and VLDL 2 ; and apoB100 in VLDL 1 , VLDL 2 , IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL 1 . In contrast, the fractional catabolic rates of VLDL 2 -apoB100 and VLDL 2 -triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL 2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL 2 - and IDL-apoB100 concentrations., Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL 1 ) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL 2 , IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m 2 ) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3 , TM6SF2 , MBOAT7 and HSD17B13 ) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA 1c , triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84-0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73-0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis.

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

Background: T-wave area dispersion (TW-Ad) is a novel electrocardiographic (ECG) repolarization marker associated with sudden cardiac death. However, limited data is available on the clinical correlates of TW-Ad. In addition, there are no previous studies on cardiovascular drug effects on TW-Ad. In this study, we examined the relation between TW-Ad and left ventricular mass. We also studied the effects of four commonly used antihypertensive drugs on TW-Ad., Methods: A total of 242 moderately hypertensive males (age, 51±6 years; office systolic/diastolic blood pressure during placebo, 153±14/100±8 mmHg), participating in the GENRES study, were included. Left ventricular mass index was determined by transthoracic echocardiography. Antihypertensive four-week monotherapies (a diuretic, a beta-blocker, a calcium channel blocker, and an angiotensin receptor antagonist) were administered in a randomized rotational fashion. Four-week placebo periods preceded all monotherapies. The average value of measurements (over 1700 ECGs in total) from all available placebo periods served as a reference to which measurements during each drug period were compared., Results: Lower, i.e. risk-associated TW-Ad values correlated with a higher left ventricular mass index (r = -0.14, p = 0.03). Bisoprolol, a beta-blocker, elicited a positive change in TW-Ad (p = 1.9×10-5), but the three other drugs had no significant effect on TW-Ad., Conclusions: Our results show that TW-Ad is correlated with left ventricular mass and can be modified favorably by the use of bisoprolol, although demonstration of any effects on clinical endpoints requires long-term prospective studies. Altogether, our results suggest that TW-Ad is an ECG repolarization measure of left ventricular arrhythmogenic substrate., Competing Interests: The authors have declared that no competing interests exist.

Background: Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear., Objective: This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes., Methods: The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period., Results: Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL 1 triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in "remnant-like particles" cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL 2 cholesterol by 50% (P < .0001) and VLDL 2 triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01)., Conclusion: Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals., (Copyright © 2020. Published by Elsevier Inc.)

Background: Electrocardiographic (ECG) left ventricular hypertrophy (LVH) is an established risk factor for cardiovascular events. However, limited data is available on the prognostic values of different ECG LVH criteria specifically to sudden cardiac death (SCD). Our goal was to assess relationships of different ECG LVH criteria to SCD., Methods: Three traditional and clinically useful (Sokolow-Lyon, Cornell, R aVL ) and a recently proposed (Peguero-Lo Presti) ECG LVH voltage criteria were measured in 5730 subjects in the Health 2000 Survey, a national general population cohort study. Relationships between LVH criteria, as well as their selected composites, to SCD were analyzed with Cox regression models. In addition, population-attributable fractions for LVH criteria were calculated., Results: After a mean follow-up of 12.5 ± 2.2 years, 134 SCDs had occurred. When used as continuous variables, all LVH criteria except for R aVL were associated with SCD in multivariable analyses. When single LVH criteria were used as dichotomous variables, only Cornell was significant after adjustments. The dichotomous composite of Sokolow-Lyon and Cornell was also significant after adjustments (hazard ratio for SCD 1.82, 95% confidence interval 1.20-2.70, P = 0.006) and was the only LVH measure that showed statistically significant population-attributable fraction (11.0%, 95% confidence interval 1.9-19.2%, P = 0.019)., Conclusions: Sokolow-Lyon, Cornell, and Peguero-Lo Presti ECG, but not R aVL voltage, are associated with SCD risk as continuous ECG voltage LVH variables. When SCD risk assessment/adjustment is performed using a dichotomous ECG LVH measure, composite of Sokolow-Lyon and Cornell voltages is the preferred option., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Our aim was to develop an automated detection method, for prescreening purposes, of early repolarization (ER) pattern with slur/notch configuration in electrocardiogram (ECG) signals using a waveform prototype-based feature vector for supervised classification., Approach: The feature vectors consist of fragments of the ECG signal where the ER pattern is located, instead of abstract descriptive variables of ECG waveforms. The tested classifiers included linear discriminant analysis, k-nearest neighbor algorithm, and support vector machine (SVM)., Main Results: SVM showed the best performance in Friedman tests in our test data including 5676 subjects representing 45 408 leads. Accuracies of the different classifiers showed results well over 90%, indicating that the waveform prototype-based feature vector is an effective representation of the differences between ECG signals with and without the ER pattern. The accuracy of inferior ER was 92.74% and 92.21% for lateral ER. The sensitivity achieved was 91.80% and specificity was 92.73%., Significance: The algorithm presented here showed good performance results, indicating that it could be used as a prescreening tool of ER, and it provides an additional identification of critical cases based on the distances to the classifier decision boundary, which are close to the 0.1 mV threshold and are difficult to label.

Objective: The aim of this study was to compare the predictive value of ECG abnormalities for atrial fibrillation in nonhypertensive versus hypertensive individuals., Methods: We recorded ECG and measured conventional cardiovascular risk factors in a nationwide population-based sample of 5813 Finns. We divided the participants into nonhypertensive (n = 3148) and hypertensive (n = 2665) individuals and followed the participants for incident atrial fibrillation events. We evaluated the predictive ability of 12 ECG abnormalities for atrial fibrillation using multivariable-adjusted Fine-Gray models., Results: During a follow-up of 11.9 ± 2.9 years, 111 nonhypertensive and 301 hypertensive participants developed atrial fibrillation. Negative T wave in lateral leads predicted atrial fibrillation in both nonhypertensive [hazard ratio (HR), 4.59; 95% confidence interval (95% CI) 1.84-11.44] and hypertensive participants (HR, 1.81; 95% CI 1.16-2.84). In nonhypertensive participants, 1-SD increments in corrected QT interval (HR, 1.42; 95% CI, 1.18-1.71) and T-wave amplitude in lead augmented vector R (aVR) (HR, 1.40; 95% CI, 1.10-1.80) were related to atrial fibrillation. In hypertensive participants, prolonged PR interval (HR, 1.59; 95% CI 1.05-2.41), prolonged P-wave duration (HR, 1.43; 95% CI 1.07-1.91), left ventricular hypertrophy by Sokolow-Lyon criteria (HR, 1.55; 95% CI, 1.12-2.14) and poor R-wave progression (HR, 1.59; 95% CI, 1.02-2.48) predicted atrial fibrillation. Corrected QT interval and T-wave amplitude in lead aVR were stronger predictors of atrial fibrillation in nonhypertensive than in hypertensive participants. ECG abnormalities improved risk prediction only marginally (delta area under receiver-operating-characteristic curve = 0.000-0.005)., Conclusion: Several ECG abnormalities associate with incident atrial fibrillation in hypertensive and nonhypertensive individuals but provide only marginal incremental predictive value. Corrected QT interval and T-wave amplitude in lead aVR may relate stronger to incident atrial fibrillation in nonhypertensive than in hypertensive individuals.

Background: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported., Methods: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10 - 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES., Results: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (β = - 4.8%, P = 9.6 × 10 - 9 for systolic and β = - 4.3%, P = 2.2 × 10 - 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10 - 5 . The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (β = - 0.8%, P = 0.4 for systolic and β = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (β = - 7.6 g/m 2 , P = 0.02)., Conclusions: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10 -8 ), we found suggestive evidence (P<5 × 10 -6 ) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Background: We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population., Methods and Results: TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9±12.5 years) participating in the Health 2000 Study-an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7±13.7 years; mean follow-up, 8.8±1.1 years). During follow-up (7.7±1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32±0.36 versus 0.60±0.19; P <0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (≤0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4; P <0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4; P <0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5; P <0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; P <0.05)., Conclusion: Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population., (© 2018 American Heart Association, Inc.)

Objective: To define the prevalence and prognosis of ECG abnormalities in hypertensive individuals., Methods: ECG, blood pressure and other cardiovascular risk factors were recorded in a nationwide population sample of 5800 Finns. The presence of 15 ECG abnormalities was evaluated. Participants were divided into categories by blood pressure and followed for coronary heart (CHD) and cardiovascular disease (CVD) events., Results: Mean follow-up was 10.4 ± 2.2 years. The age- and sex-adjusted prevalence rates of ECG abnormalities were generally higher in the hypertensive participants than in normotensive individuals. In multivariable-adjusted Cox models, the following ECG abnormalities predicted CHD in hypertensive participants: left ventricular hypertrophy (LVH) by Sokolow-Lyon criteria [hazard ratio, 1.47; 95% confidence interval (CI), 1.07-2.01; P = 0.02], LVH with ST-depression and negative T wave (ST/T changes) (hazard ratio, 2.31; 95% CI, 1.20-4.43, P = 0.01), ST/T changes (hazard ratio, 2.12; 95% CI, 1.34-3.36; P = 0.001), positive T wave in lead aVR (AVRT+) (hazard ratio, 1.74; 95% CI, 1.15-2.64; P = 0.009) and poor R-wave progression (hazard ratio, 2.02; 95% CI, 1.27-3.22; P = 0.003). These ECG abnormalities were also significant predictors of CVD in hypertensive participants (P ≤ 0.03 for all). Nonspecific intraventricular conduction delay predicted CVD in the whole population (hazard ratio, 1.50; 95% CI, 1.06-2.13; P = 0.02). Prolonged QT interval, abnormal P-wave indices, left axis deviation and early repolarization pattern were not associated with CHD or CVD., Conclusion: ECG abnormalities are highly prevalent in hypertensive individuals. LVH is still the cornerstone of cardiovascular risk assessment in hypertensive patients. The additional assessment of ST/T changes, AVRT+ and poor R-wave progression in ECGs could improve risk prediction in hypertensive patients.

Background: Heterogeneity of depolarization and repolarization underlies the development of lethal arrhythmias., Objective: We investigated whether quantification of spatial depolarization and repolarization heterogeneity identifies individuals at risk for sudden cardiac death (SCD)., Methods: Spatial R-, J-, and T-wave heterogeneity (RWH, JWH, and TWH, respectively) was analyzed using automated second central moment analysis of standard digital 12-lead electrocardiograms in 5618 adults (2588, 46% men; mean ± SEM age 50.9 ± 0.2 years), who took part in the epidemiological Health 2000 Survey as representative of the entire Finnish adult population., Results: During the follow-up period of 7.7 ± 0.2 years, a total of 72 SCDs occurred (1.3%), with an average yearly incidence rate of 0.17% per year. Increased RWH, JWH, and TWH in left precordial leads (V4-V6) were univariately associated with SCD (P < .001 for each). When adjusted with standard clinical risk markers, JWH and TWH remained independent predictors of SCD. Increased TWH (≥102 µV) was associated with a 1.7-fold adjusted relative risk for SCD (95% confidence interval [CI] 1.0-2.9; P = .048) and increased JWH (≥123 µV) with a 2.0-fold adjusted relative risk for SCD (95% CI 1.2-3.3; P = .006). When both TWH and JWH were above the threshold, the adjusted relative risk for SCD was 2.9-fold (95% CI 1.5-5.7; P = .002). When RWH (≥470 µV), JWH, and TWH were all above the threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI 1.4-7.1; P = .009)., Conclusion: Second central moment analysis of standard resting 12-lead electrocardiographic morphology provides an ultrarapid means for the automated measurement of spatial RWH, JWH, and TWH, enabling analysis of high subject volumes and screening for SCD risk in the general population., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The identification of patients at risk for sudden cardiac death (SCD) is still a significant challenge to clinicians and scientists. Noninvasive identification of high-risk patients has been of great interest, and several ventricular depolarization and repolarization abnormalities in the standard 12-lead electrocardiogram (ECG) have been associated with increased vulnerability to lethal ventricular arrhythmias. Several benign and pathological conditions can induce changes in repolarization detected as alteration of the ST segment or T wave. Changes in the ST segment and T waves can be early markers of an underlying cardiovascular disease, and even minor ST-T abnormalities have predicted reduced survival and increased risk of SCD in the adult population. In this review, we will discuss the current knowledge of the SCD risk with standard 12-lead ECG T wave abnormalities in the general population, and possible T wave changes in various cardiac conditions predisposing to SCD., (© 2015 Wiley Periodicals, Inc.)

Background: Early repolarization (ER) is defined as an elevation of the QRS-ST junction in at least two inferior or lateral leads of the standard 12-lead electrocardiogram (ECG). Our purpose was to create an algorithm for the automated detection and classification of ER., Methods: A total of 6,047 electrocardiograms were manually graded for ER by two experienced readers. The automated detection of ER was based on quantification of the characteristic slurring or notching in ER-positive leads. The ER detection algorithm was tested and its results were compared with manual grading, which served as the reference., Results: Readers graded 183 ECGs (3.0%) as ER positive, of which the algorithm detected 176 recordings, resulting in sensitivity of 96.2%. Of the 5,864 ER-negative recordings, the algorithm classified 5,281 as negative, resulting in 90.1% specificity. Positive and negative predictive values for the algorithm were 23.2% and 99.9%, respectively, and its accuracy was 90.2%. Inferior ER was correctly detected in 84.6% and lateral ER in 98.6% of the cases., Conclusions: As the automatic algorithm has high sensitivity, it could be used as a prescreening tool for ER; only the electrocardiograms graded positive by the algorithm would be reviewed manually. This would reduce the need for manual labor by 90%., (© 2014 Wiley Periodicals, Inc.)

Objective: Left ventricular hypertrophy (LVH) is a strong risk factor for cardiovascular events. ECG is the most widely used method for LVH detection. Despite the abundance of ECG LVH criteria, their prognostic values have been compared in only a few studies, and little has been known about how sex modifies the prognostic value of LVH. We assessed the relationship between ECG LVH and incident cardiovascular events in the general population., Methods: Several ECG LVH criteria were measured in 3059 women and 2456 men participating in the Health 2000 Study - a national general population survey. Association between ECG LVH and cardiovascular events were analyzed with Cox proportional-hazards models., Results: ECG LVH was more prevalent in women than in men when measured with Cornell-based criteria, but less prevalent or nondifferent when measured with other criteria. The association between ECG LVH and events showed higher hazard ratios for women than in men. Sex × LVH interaction terms were statistically significant in part of the LVH criteria. In adjusted Cox models, Sokolow-Lyon voltage performed the best. The composite of Sokolow-Lyon voltage and Cornell voltage was statistically significantly associated with events in both sexes., Conclusion: Sex affects both the prevalence rates and prognostic values of ECG LVH criteria in the general population, while showing higher prognostic value of ECG LVH in women than in men. For clinical use, the composite of the Sokolow-Lyon voltage and the Cornell voltage seems to be a good option.

Background: QRS transition zone is related to the electrical axis of the heart in the horizontal plane and is easily determined from the precordial leads of a standard 12-lead ECG. However, whether delayed QRS transition, or clockwise rotation of the heart, carries prognostic implications and predicts sudden cardiac death (SCD) is unclear., Objective: The purpose of this study was to study whether delayed transition is associated with mortality and SCD., Methods: We evaluated 12-lead ECGs of 10,815 Finnish middle-aged subjects from the general population (52% men, mean age 44 ± 8.5 years) and followed them for 30 ± 11 years. Main end-points were mortality and SCD., Results: Delayed QRS transition at lead V4 or later occurred in 1770 subjects (16.4%) and markedly delayed transition at lead V5 or later in 146 subjects (1.3%). Delayed transition zone was associated with older age, male gender, higher body mass index, hypertension, baseline cardiovascular disease, leftward shift of the frontal QRS axis, wider QRS-T angle, and ECG left ventricular hypertrophy. After adjusting for several clinical and ECG variables, delayed transition was associated with overall mortality (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.07-1.22, P < .001) and SCD (HR 1.23, 95% CI 1.03-1.47, P = .029). Markedly delayed transition at V5 or later predicted significantly SCD (HR 1.89, 95% CI 1.18-3.03, P = .008) and all-cause mortality (HR 1.30, 95% CI 1.07-1.58, P = .01). However, further adjustments for repolarization abnormalities attenuated this effect., Conclusion: Delayed QRS transition in the precordial leads of an ECG seems to be a novel ECG risk marker for SCD. In particular, markedly delayed transition was associated with significantly increased risk of SCD, independent of confounding factors., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Early repolarization (ER) in the inferior/lateral leads predicts mortality, but whether ER is a specific sign of increased risk for arrhythmic events is not known., Objective: The purpose of this study was to study the association of ER and arrhythmic events and nonarrhythmic morbidity and mortality., Methods: We assessed the prognostic significance of ER in a community-based general population of 10,846 middle-aged subjects (mean age 44 ± 8 years). The end-points were sustained ventricular tachycardia or resuscitated ventricular fibrillation (VT-VF), arrhythmic death, nonarrhythmic cardiac death, new-onset atrial fibrillation (AF), hospitalization for congestive heart failure, or coronary artery disease during mean follow-up of 30 ± 11 years. ER was defined as ≥0.1-mV elevation of J point in either inferior or lateral leads., Results: After including all risk factors of cardiac mortality and morbidity in Cox regression analysis, inferior ER (prevalence 3.5%) predicted VF-VT events (n = 108 [1.0%]) with a hazard ratio (HR) of 2.2 (95% confidence interval [CI] 1.1-4.5, P = .03) but not nonarrhythmic cardiac death (n = 1235 [12.2%]), AF (n = 1659 [15.2%]), congestive heart failure (n = 1752 [16.1%]), or coronary artery disease (n = 3592 [32.9%]) (P = NS for all). Inferior ER predicted arrhythmic death in cases without other QRS complex abnormalities (multivariate HR 1.68, 95 % CI 1.10-2.58, P = .02) but not in those with ER and other coexisting abnormalities in QRS morphology (HR 1.30, 95% CI 0.86-1.96, P = .22)., Conclusion: ER in the inferior leads, especially in cases without other QRS complex abnormalities, predicts the occurrence of VT-VF but not nonarrhythmic cardiac events, suggesting that ER is a specific sign of increased vulnerability to ventricular tachyarrhythmias., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Background: Previous population studies have found an association between electrocardiographic T-wave morphology parameters and cardiovascular mortality, but their relationship to sudden cardiac death (SCD) is not clear. To our knowledge, there are no follow-up studies assessing the association between electrocardiographic T-wave peak to T-wave end interval (TPE) and SCD. We assessed the predictive value of electrocardiographic T-wave morphology parameters and TPE for SCD in an adult general population sample., Methods and Results: A total of 4 T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, T-wave residuum) as well as TPE were measured from digital standard 12-lead ECGs in 5618 adults (46% men; mean age 50.9±12.5 years) participating in the Finnish population-based Health 2000 Study. After a mean follow-up time of 7.7±1.4 years, 72 SCDs had occurred. In univariable analyses, all T-wave morphology parameters were associated with an increased SCD risk. In multivariable Cox models, T-wave morphology dispersion and total cosine R-to-T remained as predictors of SCD, with T-wave morphology dispersion showing the highest SCD risk (hazard ratio of 1.4 [95% confidence interval 1.1-1.7, P=0.001] per 1 SD increase in the loge T-wave morphology dispersion). In contrast, TPE was not associated with SCD in univariable or multivariable analyses., Conclusions: Electrocardiographic T-wave morphology parameters describing the 3-dimensional shape of the T-wave stratify SCD risk in the general population, but we did not find an association between TPE and SCD.

Background: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases., Objective: To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP., Methods: We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages., Results: Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance., Conclusions: In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations., (Copyright © 2012 Heart Rhythm Society. All rights reserved.)

Background: T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown., Objective: To identify common genetic variants that affect the duration of the TPE interval in the general population., Methods: We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study., Results: We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes., Conclusion: The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Various models for organising tactical emergency medicine support (TEMS) in law enforcement operations exist. In Helsinki, TEMS is organised as an integral part of emergency medical service (EMS) and applied in hostage, siege, bomb threat and crowd control situations and in other tactical situations after police request. Our aim was to analyse TEMS operations, patient profile, and the level of on-site care provided., Methods: We conducted a retrospective cohort study of TEMS operations in Helsinki from 2004 to 2009. Data were retrieved from EMS, hospital and dispatching centre files and from TEMS reports., Results: One hundred twenty TEMS operations were analysed. Median time from dispatching to arrival on scene was 10 min [Interquartile Range (IQR) 7-14]. Median duration of operations was 41 min (IQR 19-63). Standby was the only activity in 72 operations, four patients were dead on arrival, 16 requests were called off en route and patient examination or care was needed in 28 operations. Twenty-eight patients (records retrieved) were alive on arrival and were classified as trauma (n = 12) or medical (n = 16). Of traumas, two sustained a gunshot wound, one sustained a penetrating abdominal wound, three sustained medium severity injuries and nine sustained minor injuries. There was neither on-scene nor in-hospital mortality among patients who were alive on arrival. The level of on-site care performed was basic life support in all cases., Conclusions: The results showed that TEMS integrated to daily EMS services including safe zone working only was a feasible, rapid and efficient way to provide medical support to law enforcement operations., (© 2011 The Authors Acta Anaesthesiologica Scandinavica © 2011 The Acta Anaesthesiologica Scandinavica Foundation.)

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive myocardial disorder caused by mutations of desmosomal cell adhesion proteins. The prevalence of these variants in the general population is unknown., Objective: This study examined the spectrum and population prevalence of desmosomal mutations predisposing to ARVC in Finland., Methods: We screened 29 Finnish ARVC probands for mutations in the DSP, DSG2, and DSC2 genes. All Finnish-type ARVC-associated mutations, including those 3 previously identified in PKP2 in the same patient group, were analyzed in the population-based Health 2000 cohort of 6,334 individuals and tested for association with electrocardiographic variables., Results: We detected 2 novel mutations: DSG2 3059&#95;3062delAGAG and DSP T1373A. DSG2 3059&#95;3062delAGAG was present in a family with 5 mutation carriers. The endomyocardial samples of the DSG2 deletion carrier showed reduced immunoreactive signal for desmoglein-2, plakophilin-2, plakoglobin, and desmoplakin. DSP T1373A was found in 1 proband with typical right ventricular disease and exercise-related ventricular tachycardia. In the population sample, the collective prevalence of all 5 mutations identified in the 29 ARVC patients (PKP2 Q62K, Q59L, N613K, DSG2 3059&#95;3062delAGAG, and DSP T1373A) was 31 of 6,334 individuals, or 0.5%. The apparent founder mutation PKP2 Q59L is present in 0.3% of Finns and was previously shown to have an approximately 20% disease penetrance., Conclusion: One of 200 Finns carries a desmosomal mutation that may predispose to ARVC and its clinical sequelae. ARVC-associated mutations may thus be more prevalent in the population than expected based on the published ARVC prevalence data., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Although sudden cardiac death (SCD) is heritable, its genetic underpinnings are poorly characterized. The QT interval appears to have a graded relationship to SCD, and 35% to 45% of its variation is heritable. We examined the relationship among recently reported common genetic variants, QT interval, and SCD., Methods and Results: We genotyped 15 common (minor allele frequency >1%) candidate single nucleotide polymorphisms (SNPs), based on association with the QT interval in prior studies, in individuals in 2 cohort studies (Health 2000, n = 6597; Mini-Finland, n = 801). After exclusions, we identified 116 incident SCDs from the remaining sample (n = 6808). We constructed a QT genotype score (QT(score)) using the allele copy number and previously reported effect estimates for each SNP. Cox proportional hazards models adjusting for age, sex, and geographical area were used for time to SCD analyses. The QT(score) was a continuous independent predictor of the heart rate-corrected QT interval (P<10(-107)). Comparing the top with the bottom quintile of QT(score), there was a 15.6-ms higher group mean QT interval (P<10(-84)). A 10-ms increase in the observed QT interval was associated with an increased risk of SCD (hazard ratio, 1.19; 95% confidence interval, 1.07 to 1.32; P = 0.002). There was no linear relationship between QT(score) and SCD risk; although in post hoc secondary analysis there was increased risk in the top compared with the middle QT(score) quintile (hazard ratio, 1.92; 95% confidence interval, 1.05 to 3.58; P = 0.04)., Conclusions: Our study strongly replicates the relationship between common genetic variants and the QT interval and confirms the relationship between the QT interval and SCD but does not show evidence for a linear relationship between QT(score) and SCD risk.

Objectives: This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts., Background: There is growing recognition that ERP is associated with adverse outcomes., Methods: Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk., Results: ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047)., Conclusions: ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Dispatching centres were fused into one of the 112 entity, which caused concerns regarding whether the medical calls could be processed effectively also in the new centre. We evaluated the effects of the reform on key performance criteria in medical calls., Methods: This observational study in the Helsinki Dispatching Centre consisted of two periods: Period I 2 years before the reform and Period II 2 years after. The main outcome measures were answering and call processing times, accuracy of risk assessment and appropriate use of ambulances., Results: In Period I (n=574,276), 92.2% of all incoming phone calls were answered within 10 s and in Period II (n=758,022) 82.8% (P<0.0001). Time to dispatch a first responding fire unit increased from 98 to 113 s (P<0.0001) and an advanced life support unit in category A calls increased from 73 to 84 s (P<0.0001). In Period I 47.7%, 34.8% and 17.5% of phone calls were completed in <3, 3-5 and >5 min and in Period II 29.8%, 36.1% and 34.1% (P<0.0001). The number of three studied non-transportation call types and unnecessary lights-and-siren responses increased significantly (P<0.0001 and 0.0001, respectively). Neither the accuracy of risk assessment in the three studied call types nor the rate of telephone-guided cardiopulmonary resuscitation changed., Conclusions: The reform increased the total number of ambulance dispatches, prolonged answering and call processing times and had a negative effect on the appropriate use of ambulances. The accuracy of risk assessment was not affected. Evidence-based data should be the basis for the future as dispatching centre processes are shown to be vulnerable during organisational reforms.

Background: Single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels and nitric oxide synthase-1 adaptor protein (NOS1AP) are associated with electrocardiographic (ECG) QT-interval duration, but the association of these SNPs with new, prognostically important ECG measures of ventricular repolarization is unknown., Objective: The purpose of this study was to examine the relationship of SNPs to ECG T-wave peak to T-wave end (TPE) interval and T-wave morphology parameters., Methods: We studied 5,890 adults attending the Health 2000 Study, a Finnish epidemiologic survey. TPE interval and four T-wave morphology parameters were measured from digital 12-lead ECGs and related to the seven SNPs showing a phenotypic effect on QT-interval duration in the Health 2000 Study population., Results: In multivariable analyses, the KCNH2 K897T minor allele was associated with a 1.2-ms TPE-interval shortening (P = .00005) and the KCNH2 intronic rs3807375 minor allele was associated with a 0.8-ms TPE-interval prolongation (P = .001), whereas the KCNE1 D85N variant had no TPE-interval effect (P = .20). NOS1AP minor alleles (rs2880058, rs4657139, rs10918594, rs10494366) were associated with a shorter TPE interval (effects from 0.5 to 0.8 ms, P from .032 to .002), which resulted from their stronger effects on QT(peak) than QT(end) interval. None of the SNPs showed a consistent association with T-wave morphology parameters., Conclusion: KCNH2 K897T and rs3807375 as well as the four studied NOS1AP variants have modest effects on ECG TPE interval but are not related to T-wave morphology measures. The previously observed prognostic value of T-wave morphology parameters likely is not based on these SNPs., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: We examined the effect of the change from paper records to the electronic patient records (EPRs) on ambulance call duration., Methods: We retrieved call duration times 6 months before (group 1) and 6 months after (group 2) the introduction of EPR. Subgroup analysis of group 2 was fulfilled depending whether the calls were made during the first or last 3 months after EPR introduction., Results: We analyzed 37 599 ambulance calls (17 950 were in group 1 and 19 649 were in group 2). The median call duration in group 1 was 48 minutes and in group 2 was 49 minutes (P = .008). In group 2, call duration was longer during the first 3 months after EPR introduction. In multiple linear regression analysis, urgency category (P < .0001), unit level (P < .0001), and transportation decision (P < .0001) influenced the call duration. The documentation method was not a significant factor., Conclusions: Electronic patient record system can be implemented in an urban ambulance service in such a way that documentation method does not become a significant factor in determining call duration in the long run. Temporary performance drop during the first 3 months after introduction was noticed, reflecting adaptation process to a new way of working.

Background: The predictive value of ECG QT interval for mortality in the general population has been weak. Only a few population studies on the predictive value of ECG T-wave morphology parameters for mortality have been reported., Objective: The purpose of this study was to examine the predictive value of ECG QT interval and T-wave morphology parameters for all-cause and cardiovascular mortality in the general population., Methods: The prognostic values of ECG QT interval and four T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, T-wave residuum) were assessed in 5,917 adults (45% men; age 52 +/- 14 years) participating in the Finnish population-based Health 2000 Study., Results: After a mean follow-up of 5.9 +/- 0.8 years, 335 deaths had occurred, including 131 cardiovascular deaths. QT interval and, with a few exceptions, all T-wave morphology parameters were significant univariate mortality predictors. In men, in Cox multivariate analyses, principal component analysis ratio and T-wave morphology dispersion remained as independent predictors of all-cause and cardiovascular mortality, with the above-median T-wave morphology dispersion group showing the highest risk of cardiovascular death (hazard ratio [HR] 4.4, 95% confidence interval [CI] 2.1-9.4). In women, independent mortality predictors were total cosine R-to-T (cardiovascular mortality) and T-wave residuum (all-cause and cardiovascular mortality), with the above-median T-wave residuum group showing the highest risk of cardiovascular death (HR 2.2, 95% CI 1.1-4.2)., Conclusion: In the general population, T-wave morphology parameters, but not heart rate-corrected QT interval, provide independent prognostic information on mortality. The prognostic value of T-wave morphology parameters is specifically related to cardiovascular mortality and seems to be gender specific.

Objectives: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample., Methods: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population., Results: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models., Conclusions: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Background and Aim: Hypertension-induced left ventricular structural remodelling associates with repolarization abnormalities. We investigated if antihypertensive drugs can modulate ventricular repolarization., Methods: A total of 183 hypertensive men received for 4 weeks drugs (losartan 50 mg, bisoprolol 5 mg, amlodipine 5 mg, hydrochlorothiazide (HCTZ) 25 mg) in a randomized order, separated by 4-week placebo periods. Electrocardiograms (ECG) were recorded at the end of placebo and drug periods. Measurements of repolarization duration (QT intervals), repolarization heterogeneity (T-wave peak to T-wave end (TPE) intervals), and T-wave morphology (T-wave principal component analysis (PCA) ratio, T-wave morphology dispersion (TMD), and total cosine R-to-T (TCRT)) during each drug were compared to placebo measurements., Results: Losartan and bisoprolol shortened maximum and mean rate-adjusted QT intervals as well as mean TPE interval, decreased TMD, and increased TCRT. Losartan also shortened precordial maximum TPE interval and decreased PCA ratio. Amlodipine had no repolarization effects, whereas HCTZ prolonged precordial maximum TPE interval and mean TPE interval., Conclusion: Losartan and bisoprolol have beneficial short-term ECG repolarization effects. Amlodipine seems to have no repolarization effects. HCTZ seems to prolong the ECG TPE interval, potentially reflecting increased repolarization heterogeneity. These findings show that antihypertensive drugs may relatively rapidly and treatment-specifically modulate ECG markers of ventricular repolarization.

Aims: Long QT syndrome (LQTS) is an inherited arrhythmia disorder with an estimated prevalence of 0.01%-0.05%. In Finland, four founder mutations constitute up to 70% of the known genetic spectrum of LQTS. In the present survey, we sought to estimate the actual prevalence of the founder mutations and to determine their effect sizes in the general Finnish population., Methods and Results: We genotyped 6334 subjects aged > or =30 years from a population cohort (Health 2000 study) for the four Finnish founder mutations using Sequenom MALDI-TOF mass spectrometry. The electrocardiogram (ECG) parameters were measured from digital 12-lead ECGs, and QT intervals were adjusted for age, sex, and heart rate using linear regression. A total of 27 individuals carried one of the founder mutations resulting in their collective prevalence estimate of 0.4% (95% CI 0.3%-0.6%). The KCNQ1 G589D mutation (n=8) was associated with a 50 ms (SE 7.0) prolongation of the adjusted QT interval (P=9.0x10(-13)). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1x10(-6))., Conclusion: In Finland 1 individual out of 250 carries a LQTS founder mutation, which is the highest documented prevalence of LQTS mutations that lead to a marked QT prolongation.

Objective: Arterial hypertension often leads to an increase in left ventricular mass (LVM). Marked left ventricular hypertrophy (LVH) is associated with potentially arrhythmogenic ventricular repolarization abnormalities, which may contribute to the increased risk of sudden cardiac death in this disorder. We studied whether electrocardiographic repolarization changes are already detectable in mild LVM increase associated with hypertension., Methods: In 220 men (mean age 51+/-6 years) attending the GENRES hypertension study, we measured QT intervals (QTend and QTpeak), T-wave peak to T-wave end (TPE) intervals, and novel T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, and T-wave residuum) from a digital standard 12-lead electrocardiogram, and related them to echocardiographically determined LVM., Results: In this group of moderately hypertensive men, the mean LVM index (LVMI; LVM divided by body surface area) was 99+/-19 g/m2, with only 18% of the subjects showing evidence of echocardiographic LVH (LVMI>116 g/m2). LVMI correlated significantly with QT intervals (r=0.16-0.21, P=0.018-0.002), TPE intervals (r=0.23-0.27, P<0.001), and T-wave morphology parameters (r=0.22-0.39, P<0.001). Except for the QTpeak interval, the relationship between LVMI and electrocardiographic repolarization parameters was independent in multivariate analyses., Conclusion: Altered electrocardiographic ventricular repolarization, indicating reduced repolarization reserve and possibly increased repolarization heterogeneity, is already present in hypertensive men with only mild LVM increase. At a population level, this may carry important risk implications for the large group of hypertensive patients.